Remedy for erection failure comprising fused pyridazine compound

ABSTRACT

The present invnetion provides a remedy for erectile dysfunction. The active ingredient thereof is a fused pyridazine compound represented by the following formula (I) or a pharmacologically acceptable salt thereof:(wherein the ring C represents a 5 or 6 membered ring optionally having hetero atom(s); n is an integer of from 1 to 4; R1 represents a hydrogen, a halogen, a cyano, etc.; A represents a hydrogen, a halogen, an optionally substituted amino, etc.; X represents a group represented by the formula -N=, etc.; and Y represents the formula -CO-, an optionally substituted amino, etc).

This application is the national phase under 35 U.S.C. §371 of prior PCTInternational Application No. PCT/JP97/02785 which has an Internationalfiling date of Aug. 8, 1997 which designated the United States ofAmerica.

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention relates to remedies for erectile dysfunction whichcontain as the active ingredient novel fused pyridazine compounds.

2. Prior Art

It is said that the number of latent patients with erectile dysfunctionamounts to about 3,000,000 in Japan. In U.S.A., it is reported that thenumber of patients with erectile dysfunction reaches 20,000,000 and 15%of males in the fifties and about {fraction (1/3+L )} of those in thesixties suffer from this disease. In this aging society, sexualintercourse is regarded as a pleasant and emotional behavior. With theneeds for the improved quality of life, it is anticipated that erectiledysfunction will raise not only a medical problem but also a socialproblem in future. This disease is classified into organic impotencecaused by disorders in the nerves, blood vessels or muscles in the penisper se or sexual hormones and functional (psychic) impotence caused bymental or psychologic troubles. There are three factors necessary forerection, i.e., an increase in the penile arterial blood flow, theregulation of blood leakage from the penile veins, and the relaxation ofthe cavernous tissue. Erectile dysfunction arises when at least one ofthese conditions is inhibited.

The urological treatments for erectile dysfunction effected todayinvolve drug therapy and operative penile prosthesis with the use ofpenile prosthetic appliances.

As the drug therapy, it is possible to inject papaverine hydrochlorideor prostaglandin E1 into the penile cavernous tissue. However, thistreatment is scarcely performed today, since it is not allowed in Japanthat a patient gives an injection to himself and it is impossible inpractice to go for a doctor every time he has coitus. In addition, theinjection of papaverine hydrochloride would cause, though exceptionally,a painful symptom called priapism. Thus, the treatments with theexisting drugs are not practically usable. Accordingly, it has beenurgently desired to develop a drug therapy therefor which is clinicallyefficacious in practice.

In 1984, Bowman and Drummond reported that a selective cyclic GMPphosphodiesterase inhibitor M&B22948 (zaprinast) increased cyclic GMP inthe tissue and relaxed the bovine retractor penis muscle (Cyclic GMPmediates neurogenic relaxation in the bovine retractor penis muscle, Br.J. Pharmacol., RI, 665-674, 1984). Subsequently, other workers havereported one after another the relaxation of the penis cavernosum byincreasing cyclic GMP in the tissue (Int. J. Impotence Res., 4, 85-93,1992; J. Urol., 147, 1650-1655, 1992; and N. Engl. J. Med., 32S, 90-94,1992). However, none of the compounds employed in these studies can besatisfactorily employed clinically due to poor efficacy, etc.

DISCLOSURE OF THE INVENTION

Under these circumstances, the present inventors have conductedextensive studies and consequently found out that fused pyridazinecompounds represented by the formula (I), which are disclosed inWO96/05176 show a high selectivity for phosphodiesterase type v which isan enzyme capable of degrading cyclic GMP and a potent inhibitoryeffect, thus completing the present invention:

(wherein the ring C represents an unsaturated 5 or 6 membered ringoptionally having hetero atom(s); n is 0 or an integer of from 1 to 4;R¹ represents a halogen, an optionally substituted lower alkyl, anoptionally substituted lower alkoxy, an optionally substitutedcycloalkyl, a nitro, a cyano, a group represented by the formula —NR²R³(wherein R² and R³are the same as or different from each other andrepresent a hydrogen, an optionally substituted lower alkyl, an acyl, anoptionally substituted arylalkyl or an optionally substitutedheteroarylalkyl, or R² and R³ together with the nitrogen atom to whichthey are bonded may form a ring, and the ring may be substituted), agroup represented by the formula —O—R⁹ (wherein R⁹represents a hydrogen,an optionally substituted lower alkyl, an acyl, an optionallysubstituted arylalkyl or an optionally substituted heteroarylalkyl), agroup represented by the formula —S—R¹⁰ (wherein R¹⁰ represents ahydrogen, an optionally substituted lower alkyl, an acyl, an optionallysubstituted arylalkyl, or an optionally substituted heteroarylalkyl), agroup represented by the formula;

(wherein R¹¹ represents a hydrogen, a lower alkyl or an amino; and m is0 or an integer of 1 or 2) or an optionally protected carboxy, providedthat when n is 2 to 4, then R¹s may independently represent the abovesubstituents;

A represents a hydrogen, a halogen, a group represented by the formula—NR⁴R⁵ (wherein R⁴ and R⁵ are the same as or different from each otherand represent a hydrogen, an optionally substituted lower alkyl, anacyl, an optionally substituted arylalkyl or an optionally substitutedheteroarylalkyl, or R⁴ and R⁵ together with the nitrogen atom to whichthey are bonded may form a ring, and the ring may be substituted), anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted arylalkyl or an optionally substitutedheteroarylalkyl;

X represents a group represented by the formula —NR⁶— (wherein R⁶represents a hydrogen, an optionally substituted lower alkyl, anoptionally substituted arylalkyl or an optionally substitutedheteroarylalkyl) or a group represented by the formula —N═;

Y represents a group represented by the formula —CO— or —C(B)═ [whereinB represents a hydrogen, a halogen, a group represented by the formula—NR⁷R⁸ (wherein R⁷ and R⁸ are the same as or different from each otherand represent a hydrogen, an optionally substituted lower alkyl, anacyl, an optionally substituted arylalkyl or an optionally substitutedheteroarylalkyl, or R⁷ and R⁸ together with the nitrogen atom to whichthey are bonded may form a ring, and the ring may be substituted), agroup represented by the formula —O—R¹² (wherein R¹² represents ahydrogen, an optionally substituted lower alkyl, an acyl, an optionallysubstituted arylalkyl or an optionally substituted heteroarylalkyl),—S—R¹³ (wherein R¹³ represents a hydrogen, an optionally substitutedlower alkyl, an acyl, an optionally substituted arylalkyl or anoptionally substituted heteroarylalkyl), an optionally substituted aryl,an optionally substituted heteroaryl, an optionally substitutedarylalkyl or an optionally substituted heteroarylalkyl]; and

represents a double or single bond; provided that when the ring C is abenzene ring, then the case where n is 0 is excluded}.

In addition to the remedies (1) as described above, the presentinvention further provides: (2) remedies for female sexual dysfunction,dysmenorrhea or premature birth comprising as the active ingredient theabove fused pyridazine compounds or pharmacologically acceptable saltsthereof; (3) medicinal compositions comprising a therapeuticallyeffective dose of the above fused pyridazine compounds orpharmacologically acceptable salts thereof and pharmacologicallyacceptable carriers; (4) a method for treating erectile dysfunction,female sexual dysfunction, dysmenorrhea or premature birth whichcomprises administering a therapeutically effective dose of the abovefused pyridazine compounds or pharmacologically acceptable salts thereofto a patient with erectile dysfunction, female sexual dysfunction ordysmenorrhea or a patient giving premature birth; and (5) use of theabove fused pyridazine compounds or pharmacologically acceptable saltsthereof for producing remedies for erectile dysfunction, female sexualdysfunction, dysmenorrhea or premature birth.

In the definition given herein, as the unsaturated 5 or 6 membered ringoptionally having hetero atom(s) represented by the ring C, benzene,pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole,pyrazole, thiophene and furan rings may be proposed.

In the definition represented by the above formula (I), the lower alkylin the “optionally substituted lower alkyl” as used in the definition ofR¹, R^(1a), R^(1b), R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² andR¹³ means linear or branched C₁₋₆ alkyl such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl,1-ethylpropyl, isoamyl and n-hexyl. Examples of the substituent includehydroxy, nitro, amino, cyano, acyl such as acetyl and benzoyl, loweralkoxy such as methoxy and ethoxy, halogeno such as fluorine, chlorine,bromine and iodine and optionally protected carboxy. Either one or moreof these substituents may be attached to one or more carbon atoms in thelower alkyl.

The lower alkoxy in the “optionally substituted lower alkoxy” as used inthe definition of R¹, R^(1a) and R^(1b) means those derived from theabove-mentioned lower alkyl, for example, methoxy, ethoxy and propoxy.Examples of the substituent include hydroxy, nitro, amino, cyano, acylsuch as acetyl and benzoyl, lower alkoxy such as methoxy and ethoxy,halogeno such as fluorine, chlorine, bromine and iodine, and optionallyprotected carboxy. Either one or more of these substituents may beattached to one or more carbon atoms in the lower alkoxy.

The cycloalkyl in the “optionally substituted cycloalkyl” as used in thedefinition of R¹, R^(1a) and R^(1b) means C₃₋₈ ones. Examples of thesubstituent include hydroxy, nitro, amino, cyano, acyl such as acetyland benzoyl, lower alkoxy such as methoxy and ethoxy, halogeno such asfluorine, chlorine, bromine and iodine, and optionally protectedcarboxy. Either one or more of these substituents may be attached to oneor more carbon atoms in the cycloalkyl.

The term “acyl” as used in the definition of R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹², and R¹³ means acyl derived from aliphatic, aromatic orheterocyclic groups. Examples thereof include lower alkanoyl such asformyl, acetyl, propionyl, butyryl, valeryl, isovaleryl and pivaloyl,aroyl such as benzoyl, toluoyl and naphthoyl, and heteroaroyl such asfuroyl, nicotinoyl and isonicotinoyl. Namely, any groups derived fromvarious carboxylic acids are involved therein. Among these substituents,it is preferable to use formyl, acetyl, benzoyl, etc.

The aryl in the “optionally substituted aryl” as used in the definitionof A and B means those derived from aromatic rings such as phenyl,1-naphthyl, 2-naphthyl and anthracenyl. Examples of the substituentinclude hydroxy, nitro, amino, cyano, acyl such as acetyl and benzoyl,lower alkoxy such as methoxy and ethoxy, halogeno such as fluorine,chlorine, bromine and iodine, and optionally protected carboxy.

The heteroaryl in the “optionally substituted heteroarylalkyl” as usedin the definition of A and B means monocyclic or heterocyclic groupscontaining one or more atoms of nitrogen, sulfur, oxygen, etc. Examplesthereof include pyridyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazyl,pyrimidyl, pyridazyl, thienyl, pyranyl, isothiazolyl, isoxazolyl,furazanyl, benzothienyl, furyl, indolyl, indolizinyl, isoindolyl,benzothiazolyl, benzimidazolyl and quinazolyl. Examples of thesubstituent include hydroxy, nitro, amino, cyano, acyl such as acetyland benzoyl, lower alkoxy such as methoxy and ethoxy, halogeno such asfluorine, chlorine, bromine and iodine, and optionally protectedcarboxy.

The expression “R² and R³, R⁴ and R⁵, or R⁷ and R⁸ together with thenitrogen atom to which they are bonded may form a ring” as used in thedefinition of —NR²R³ in R¹, —NR⁴R⁵ in A and —NR⁷R⁸ in B means that R²andR³, R⁴ and R⁵, or R ⁷and R⁸ may form, together with the nitrogen atom towhich they are bonded, for example, piperidinyl, pyrrolidinyl,piperazinyl, etc. Examples of the substituent include hydroxy,optionally substitutedamino, aminoalkyl, nitro, nitroalkyl, loweralkoxy,lower alkoxyalkyl, hydroxyalkyl, optionally protected carboxy andoptionally protected carboxyalkyl. The most preferable examples of thesubstituent include hydroxy, hydroxymethyl, hydroxyethyl, carboxymethyland carboxyethyl.

The aryl in the “optionally substituted arylalkyl” as used in thedefinition of R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², R¹³ and Y meansthose derived from aromatic rings such as phenyl, 1-naphthyl, 2-naphthyland anthracenyl. The alkyl as used herein means those derived from theabove-mentioned lower alkyl. Examples of the substituent includehydroxy, nitro, amino, cyano, acyl such as acetyl and benzoyl, loweralkoxy such as methoxy and ethoxy, halogeno such as fluorine, chlorine,bromine and iodine, and optionally protected carboxy.

The heteroaryl in the “optionally substituted heteroarylalkyl” as usedin the definition of R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹², R¹³and Ymeans monocyclic or heterocyclic groups containing one or more atoms ofnitrogen, sulfur, oxygen, etc. Examples thereof include pyridyl,pyrrolyl, imidazolyl, pyrazolyl, pyrazyl, pyrimidyl, pyridazyl, thienyl,pyranyl, isothiazolyl, isoxazolyl, furazanyl, benzothienyl, furyl,indolyl, indolizinyl, isoindolyl, benzothiazolyl, benzimidazolyl andquinazolyl. The alkyl as used herein manes those derived from theabove-mentioned lower alkyl. Examples of the substituent includehydroxy, nitro, amino, cyano, acyl such as acetyl and benzoyl, loweralkoxy such as methoxy and ethoxy, halogeno such as fluorine, chlorine,bromine and iodine, and optionally protected carboxy.

The term “halogeno” as used in the definition of R¹, R^(1a), R^(1b),R¹², R¹³ and R¹⁴ means fluorine, chlorine, bromine, iodine, etc.

Examples of the pharmacologically acceptable salts to be used in thepresent invention include inorganic acid salts such as hydrochlorides,sulfates, hydrobromides and phosphates and organic acid salts such asformates, acetates, trifluoroacetates, maleates, fumarates, tartrates,methanesulfonates, benzenesulfonates and toluenesulfonates.

Some of the compounds according to the present invention form hydrates.Needless to say, these hydrates are also included within the scope ofthe present invention.

Among the compounds according to the present invention, preferable onesare fused pyridazine compounds represented by the following formula (I)wherein the ring C is benzene or pharmacologically acceptable saltsthereof:

(wherein n, R¹, A, X, Y and

are each as defined above).

Among them, still preferable ones are fused pyridazine compoundsrepresented by the following formula (IV) or pharmacologicallyacceptable salts thereof:

(wherein B, R^(1a), R¹⁴, R¹⁵ and R¹⁶ are each as defined above).

Because of being excellent in oral absorbability and long-lastingaction, these fused pyridazine compounds or pharmacologically acceptablesalts thereof can be percutaneously, intravenously or orallyadministered for treatment without resort to injection directly into thepenile cavernosum, which makes them favorable as remedies for erectiledysfunction.

Although the compounds of the present invention may be administered inan arbitrary dose without restriction, they are usually given to anadult in a dose of from 5 μg to 100 mg, preferably from 10 to 1,000 μg,in the case of intravenous administration, or in a dose of from 1 to1,000 mg, preferably from 5 to 100 mg, in the case of oraladministration.

WO96/05176 discloses processes for producing these fused pyridazinecompounds or pharmacologically acceptable salts thereof and theirphosphodiesterase type V inhibitory activities.

Although the compounds of the present invention aim at treating maleerectile dysfunction, these compounds are also efficacious againstfemale sexual dysfunction, premature birth and dysmenorrhea.

Best Mode for Carrying Out the Invention:

The following Examples will be given to show the effects of thecompounds of the present invention.

EXAMPLE

Relaxing Effect on Extirpated Rabbit Penile Cavernosum Preparation

The penis was extirpated from a Japanese white rabbit (about 3 kg) underanesthesia with pentobarbital (50 mg/kg) administered intravenously togive a penile cavernosum preparation (about 20×1.5×1.5 mm). Thispreparation was suspended in a Magnus tube filled up withKrebs-Henseleit's nutritive solution (containing 1 PM of indomethacin)at 37° C. and a gas mixture (95% oxygen +5% carbon dioxide) was bubbledthereinto. Then the isometric tension was recorded under a load of 2 g.To stabilize the contraction, contraction caused by adding a potassiumchloride solution (final concentration: 50 mM) and washing with thenutritive solution were repeated for two times. Next, the preparationwas contracted by adding a phenylephrine solution (final concentration:10 μM). When the contraction was stabilized,4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxypiperidino)-phthalazinehydrochloride (hereinafter referred to as the compound A) was addedcumulatively at a common ratio of 10 from 1 nM to 100 μM in the finalconcentration and the tension was continuously recorded. From thedose-response curve thus formed, the medium relaxation concentration ofthe compound A on the contraction was determined. The value obtainedfrom six preparations was 4.47 μM (95% confidence limit: 1.88-10.6 μM)

TABLE 1 Conc. (μM) of Relaxation ratio Compound A (%) 0.01 17.4 ± 1.4 0.1 28.1 ± 5.1  1.0 40.8 ± 10.4 10.0 61.4 ± 5.1  100.0 90.6 ± 1.6 

PRODUCTION EXAMPLE

4-(3-Chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxypiperidino)phthalazineHydrochloride

69 g of 6-cyano-2,3-dihydro-1,4-phthaladinedione was suspended in 400 mlof phosphorus oxychloride. After adding 75 ml of diisopropylethylamine,the mixture was heated under reflux for 40 minutes. Then the excessivephosphorus oxychloride was evaporated and the residue was dissolved inmethylene chloride and poured into ice water. After filtering off theunnecessary through celite, the celite filter was washed with methylenechloride. The filtrate was extracted with methylene chloride. Theorganic layer was washed with a saturated aqueous solution of sodiumbicarbonate, dilute hydrochloric acid and brine and dried over anhydrousmagnesium sulfate. This solution was filtered by using silica gel andthe solvent was evaporated to give 66 g of6-cyano-1,4-dichlorophthalazine as a pale orange solid.

¹H-NMR(400 MHz, CDCl₃) δ: 8.24(1H, dd, J=8.5, 1.5 Hz), 8.47(1H, dd,J=8.5, 1.0 Hz), 8.68(1H, dd, J=1.5, 1.0 Hz).

66.2 g of 6-cyano-1,4-dichlorophthalazine and 92 g of3-chloro-4-methoxybenzylamine were suspended in 1,200 ml oftetrahydrofuran. After adding 250 ml of triethylamine, the resultingmixture was heated under reflux for 6 hours. The resulting crystals werefiltered off and the filtrate was evaporated. The residue was purifiedby silica gel column chromatography (toluene:tetrahydrofuran=10:1) togive 59 g of1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine as paleyellow crystals. M.p.: 213.0-214.5° C., Mass 359(MH+),

¹H-NMR(400 MHz, CDCl₃) δ: 3.87(3H, s), 4.78(2H, d, J=5.0 Hz), 5.75(1H,t, J=5.0 Hz), 6.87(1H, d, J=8.5 Hz), 7.31(1H, dd, J=8.5, 2.0 Hz),7.43(1H, d, J=2.0 Hz), 8.05(1H, dd, J=8.5, 1.5 Hz), 8.24(1H, dd, J=1.5,1.0 Hz), 8.29(1H, dd, J=8.5, 0.5 Hz). 10.0 g of1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine wasdissolved in 50 ml of N-methyl-2-piperidone. After adding 43.32 g of4-hydroxypiperidine and 10 ml of diisopropylethylamine, the resultingmixture was heated at 170° C. for 8 hours. Then ethyl acetate wag addedthereto and the resulting mixture was successively washed for threetimes with water and once with brine and dried over anhydrous magnesiumsulfate. After evaporating the solvent, the residue was purified bysilica gel column chromatography (methylene chloride:methanol=30:1) togive 10.1 g of4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxypiperidino)phthalazineas yellow crystals. M.p.: 172.0-173.5° C., Mass 424(MH+),

¹H-NMR(400 MHz, CDCl₃) δ: 1.70(1H, brs), 1.80-1.90(2H, m), 2.07-2.15(2H,m), 3.05-3.15(2H, m), 3.50-3.60(2H, m), 3.87(3H, s), 3.90-4.00(1H, m),4.74(2H, d, J=5.0 Hz), 5.41(1H, t, J=5.0 Hz), 6.87(1H, d, J=8.5 Hz),7.29(1H, dd, J=8.5, 2.0 Hz), 7.42(1H, d, J=2.0 Hz), 7.95(1H, dd, J=8.5,1.5 Hz), 8.12(1H, dd, J=1.5, 1.0 Hz), 8.21(1H, dd, J=8.5, 0.5 Hz).

10.8 g of4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxypiperidino)phthalazinewas suspended in a mixture of ethanol (60 ml) with water (30 ml) and 30ml of a 1 N aqueous solution of hydrochloric acid was added thereto.After dissolving by heating once, the mixture was cooled by allowing tostand at room temperature. The resulting crystals were collected byfiltration and hot air-dried at 80° C. overnight to give 9.37 g of thetitle compound as yellow crystals. M.p. 217-227° C. (decomp.), Mass 424(MH+),

¹H-NMR(400 MHz, CDCl₃) δ: 1.61-1.70(2H, m), 1.90-1.97(2H, m),2.97-3.04(2H, m), 3.37-3.48(2H, m), 3.70-3.79(1H, m), 3.84(3H, s),4.70(2H, d, J=5.5 Hz), 7.15(1H, d, J=8.5 Hz), 7.44(1H, dd, J=8.5, 2.0Hz), 7.59(1H, d, J=2.0 Hz), 8.23(1H, dd, J=8.5 Hz), 8.45(1H, d, J=8.5Hz), 9.33(1H, s), 10.10(1H, brs), 14.00(1H, brs)

What is claimed is:
 1. A method for treating erectile dysfunction whichcomprises administering an effective amount of a fused pyridazinecompound represented by the following formula (I) or a pharmacologicallyacceptable salt thereof, to a patient in need thereof:

wherein the ring C represents an unsaturated 5 or 6 membered ringoptionally having one heteroatom; n is 0 or an integer of from 1 to 4;R¹ represents a halogen, an optionally substituted lower alkyl, anoptionally substituted lower alkoxy, an optionally substitutedcycloalkyl, a nitro, a cyano, a group represented by the formula —NR²R³,wherein R² and R³ are the same as or different from each other andrepresent a hydrogen, an optionally substituted lower alkyl, an acyl, anoptionally substituted arylalkyl or an optionally substitutedheteroarylalkyl, or R² and R³ together with the nitrogen atom to whichthey are bonded may form a ring, and the ring may be substituted, agroup represented by the formula —O—R⁹, wherein R⁹ represents ahydrogen, an optionally substituted lower alkyl, acyl, an optionallysubstituted arylalkyl or an optionally substituted heteroarylalkyl, agroup represented by the formula —S—R¹⁰, wherein R¹⁰ represents ahydrogen, an optionally substituted lower alkyl, acyl, an optionallysubstituted arylalkyl or an optionally substituted heteroarylalkyl, agroup represented by the formula:

wherein R¹¹ represents a hydrogen, a lower alkyl or an amino; and m is 0or an integer of 1 or 2, or an optionally protected carboxy, providedthat when n is 2 to 4, then R¹s may independently represent the abovesubstituents; A represents a hydrogen, a halogen, a group represented bythe formula —NR⁴R⁵, wherein R⁴ and R⁵ are the same as or different fromeach other and represent a hydrogen, an optionally substituted loweralkyl, an acyl, an optionally substituted arylalkyl or an optionallysubstituted heteroarylalkyl, or R⁴ and R⁵ together with the nitrogenatom to which they are bonded may form a ring, and the ring may besubstituted, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted arylalkyl or an optionallysubstituted heteroarylalkyl; X represents a group represented by theformula —NR⁶—, wherein R⁶ represents a hydrogen, an optionallysubstituted lower alkyl, an optionally substituted arylalkyl or anoptionally substituted heteroarylalkyl or a group represented by theformula —N═; Y represents a group represented by the formula —CO— or—C(B)═, wherein B represents a hydrogen, a halogen, a group representedby the formula —NR⁷R⁸, wherein R⁷ and R⁸ are the same as or differentfrom each other and represent a hydrogen, an optionally substitutedlower alkyl, an acyl, an optionally substituted arylalkyl or anoptionally substituted heteroarylalkyl, or R⁷ and R⁸ together with thenitrogen atom to which they are bonded may form a ring, and the ring maybe substituted, a group represented by the formula —O—R¹², wherein R¹²represents a hydrogen, an optionally substituted lower alkyl, an acyl,an optionally substituted arylalkyl or an optionally substitutedheteroarylalkyl, a group represented by the formula —S—R¹³, wherein R¹³represents a hydrogen, an optionally substituted lower alkyl, an acyl,an optionally substituted arylalkyl or an optionally substitutedheteroarylalkyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted arylalkyl or anoptionally substituted heteroarylalkyl; and

represents a double or single bond; provided that when C is a benzenering, then the case where n is 0 is excluded.
 2. The method as set forthin claim 1, wherein the ring C is a benzene ring.
 3. The method as setforth in claim 1, wherein X is nitrogen and Y is the formula —C(B)═,wherein B represents a hydrogen, a halogen, a group represented by theformula —NR⁷R⁸, wherein R⁷ and R⁸ are the same as or different from eachother and represent a hydrogen, an optionally substituted lower alkyl,an acyl, an optionally substituted arylalkyl or an optionallysubstituted heteroarylalkyl, or R⁷ and R⁸ together with the nitrogenatom to which they are bonded may form a ring, and the ring may besubstituted, a group represented by the formula —O—R¹², wherein R¹²represents a hydrogen, an optionally substituted lower alkyl, an acyl,an optionally substituted arylalkyl or an optionally substitutedheteroarylalkyl, a group represented by the formula —S—R¹³, wherein R¹³represents a hydrogen, an optionally substituted lower alkyl, an acyl,an optionally substituted arylalkyl or an optionally substitutedheteroarylalkyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted arylalkyl or anoptionally substituted heteroarylalkyl.
 4. The method as set forth inclaim 1, wherein the ring C is a pyridine ring, X is nitrogen and Y isthe formula —C(B)═wherein B represents a hydrogen, a halogen, a grouprepresented by the formula —NR⁷R⁸, wherein R⁷ and R⁸ are the same as ordifferent from each other and represent a hydrogen, an optionallysubstituted lower alkyl, an acyl, an optionally substituted arylalkyl oran optionally substituted heteroarylalkyl, or R⁷ and R⁸ together withthe nitrogen atom to which they are bonded may form a ring, and the ringmay be substituted, a group represented by the formula —O—R¹², whereinR¹² represents a hydrogen, an optionally substituted lower alkyl, anacyl, an optionally substituted arylalkyl or an optionally substitutedheteroarylalkyl, a group represented by the formula —S—R¹³, wherein R¹³represents a hydrogen, an optionally substituted lower alkyl, an acyl,an optionally substituted arylalkyl or an optionally substitutedheteroarylalkyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted arylalkyl or anoptionally substituted heteroarylalkyl.
 5. The method as set forth inclaim 1 or 2, wherein the fused pyridazine compound is represented bythe following formula (II):

wherein R^(1a) and R^(1b) are different from each other and eachrepresents a halogen, an optionally substituted lower alkyl, anoptionally substituted lower alkoxy, an optionally substitutedcycloalkyl, a nitro, a cyano or a group represented by the formula—NR²R³, wherein R² and R³ are the same as or different from each otherand represent a hydrogen, an optionally substituted lower alkyl, anacyl, an optionally substituted arylalkyl or an optionally substitutedheteroarylalkyl, or R² and R³ together with the nitrogen atom to whichthey are bonded may form a ring, and the ring may be substituted; n is 0or an integer from 1 to 3; A represents a hydrogen, a halogen, a grouprepresented by the formula —NR⁴R⁵, wherein R⁴ and R⁵ are the same as ordifferent from each other and represent a hydrogen, an optionallysubstituted lower alkyl, an acyl, an optionally substituted arylalkyl oran optionally substituted heteroarylalkyl, or R⁴ and R⁵ together withthe nitrogen atom to which they are bonded may form a ring, and the ringmay be substituted, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted arylalkyl or anoptionally substituted heteroarylalkyl and B represents a hydrogen, ahalogen, a group represented by the formula —NR⁷R⁸, wherein R⁷ and R⁸are the same as or different from each other and represent a hydrogen,an optionally substituted lower alkyl, an acyl, an optionallysubstituted arylalkyl or an optionally substituted heteroarylalkyl, orR⁷ and R⁸ together with the nitrogen atom to which they are bonded mayform a ring, and the ring may be substituted, a group represented by theformula —O—R¹², wherein R¹² represents a hydrogen, an optionallysubstituted lower alkyl, an acyl, an optionally substituted arylalkyl oran optionally substituted heteroarylalkyl, a group represented by theformula —S—R¹³, wherein R¹³ represents a hydrogen, an optionallysubstituted lower alkyl, an acyl, an optionally substituted arylalkyl oran optionally substituted heteroarylalkyl, an optionally substitutedaryl, an optionally substituted heteroaryl, an optionally substitutedarylalkyl or an optionally substituted heteroarylalkyl.
 6. The method asset forth in claim 1 or 2, wherein the fused pyridazine compound isrepresented by the following formula (III):

wherein R^(1a) and R^(1b) are different from each other and represent ahalogen, an optionally substituted lower alkyl, an optionallysubstituted lower alkoxy, an optionally substituted cycloalkyl, a nitro,a cyano or a group represented by the formula —NR²R³, wherein R² and R³are the same as or different from each other and represent a hydrogen,an optionally substituted lower alkyl group, an acyl, an optionallysubstituted arylalkyl or an optionally substituted heteroarylalkyl, orR² and R³ together with the nitrogen atom to which they are bonded mayform a ring, and the ring may be substituted; R⁶ represents a hydrogen,an optionally substituted lower alkyl, an optionally substitutedarylalkyl or an optionally substituted heteroarylalkyl; n′ is 0 or aninteger of 1 to 3; A represents a hydrogen, a halogen, a grouprepresented by the formula —NR⁴R⁵, wherein R⁴ and R⁵ are the same as ordifferent from each other and represent a hydrogen, an optionallysubstituted lower alkyl, an acyl, an optionally substituted arylalkyl oran optionally substituted heteroarylalkyl, or R⁴ and R⁵ together withthe nitrogen atom to which they are bonded may form a ring, and the ringmay be substituted, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted arylalkyl or anoptionally substituted heteroarylalkyl.
 7. The method as set forth inclaim 1, wherein the fused pyridazine compound is represented by thefollowing formula (IV):

wherein R¹⁴, R¹⁵ and R¹⁶ are the same as or different from each otherand represent a hydrogen, a halogen, an optionally substituted loweralkyl or an optionally substituted lower alkoxy, or two of R¹⁴, R¹⁵ andR¹⁶ bonded to carbon atoms adjacent to each other may formmethylenedioxy or ethylenedioxy; R^(1a) represents a halogen, anoptionally substituted lower alkyl, an optionally substituted loweralkoxy, an optionally substituted cycloalkyl, a nitro, a cyano or agroup represented by the formula —NR²R³, wherein R² and R³ are the sameas or different from each other and represent a hydrogen, an optionallysubstituted lower alkyl, an acyl, an optionally substituted arylalkyl oran optionally substituted heteroarylalkyl, or R² and R³ together withthe nitrogen atom to which they are bonded may form a ring, and the ringmay be substituted and B represents a hydrogen, a halogen, a grouprepresented by the formula —NR⁷R⁸, wherein R⁷ and R⁸ are the same as ordifferent from each other and represent a hydrogen, an optionallysubstituted lower alkyl, an acyl, an optionally substituted arylalkyl oran optionally substituted heteroarylalkyl, or R⁷ and R⁸ together withthe nitrogen atom to which they are bonded may form a ring, and the ringmay be substituted, a group represented by the formula —O—R¹², whereinR¹² represents a hydrogen, an optionally substituted lower alkyl, anacyl, an optionally substituted arylalkyl or an optionally substitutedheteroarylalkyl, a group represented by the formula —S—R¹³, wherein R¹³represents a hydrogen, an optionally substituted lower alkyl, an acyl,an optionally substituted arylalkyl or an optionally substitutedheteroarylalkyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted arylalkyl or anoptionally substituted heteroarylalkyl.
 8. The method as set forth inclaim 1, wherein the fused pyridazine compound is represented by thefollowing formula (V):

wherein R^(1a) represents a halogen, an optionally substituted loweralkyl, an optionally substituted lower alkoxy, an optionally substitutedcycloalkyl, a nitro, a cyano or a group represented by the formula—NR²R³, wherein R² and R³ are the same as or different from each otherand represent a hydrogen, an optionally substituted lower alkyl, anacyl, an optionally substituted arylalkyl or an optionally substitutedheteroarylalkyl, or R² and R³ together with the nitrogen atom to whichthey are bonded may form a ring, and the ring may be substituted, R⁶represents a hydrogen, an optionally substituted lower alkyl, anoptionally substituted arylalkyl or an optionally substitutedheteroarylalkyl and R¹⁴, R¹⁵ and R¹⁶ are the same as or different fromeach other and represent a hydrogen, a halogen, an optionallysubstituted lower alkyl or an optionally substituted lower alkoxy, ortwo of R¹⁴, R¹⁵ and R¹⁶ bonded to carbon atoms adjacent to each othermay form methylenedioxy or ethylenedioxy.
 9. The remedy as set forth inclaim 1, wherein the compound is one selected from among the followingcompounds: 1)1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyano-phthalazine; 2)1-chloro-6-cyano-4-(2-methoxyethyl)aminophthalazine; 3)1-chloro-4-(3-chloro-4-methoxyanilino)-6-cyanophthalazine; 4)1-chloro-6-cyano-4-(4-methoxybenzyl)aminophthalazine; 5)1-chloro-4-(α-methyl-3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine;6) 1-chloro-4-(3-chloro-4-ethoxybenzyl)amino-6-cyano-phthalazine; 7)1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-trifluorophthalazine; 8)1-chloro-4-(3-chloro-4-methoxybenzyl)amino-6-(N,N-dimethylsulfamoyl)phthalazine;9) 1-(3-chloro-4-methoxybenzyl)amino-4,6,7-trichloro-phthalazine; 10)1-(3-chloro-4-methoxybenzyl)amino-4,6-dichloro-phthalazine; 11)4-chloro-1-(3-chloro-4-methoxybenzyl)amino-6-nitro-phthalazine; 12)4-chloro-1-[3-chloro-4-(4-methoxybenzyloxy)-benzyl]amino-6-cyanophthalazine;13) 4-chloro-1-(3-chloro-4-ethoxybenzyl)amino-6-cyano-phthalazine; 14)8-(3-chloro-4-methoxybenzyl)amino-5-(4-hydroxypiperidino)pyrido[2,3-d]pyridazine;15)4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxypiperidino)phthalazine;16)1-(4-carbamoylpiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine;17)6-chloro-4-(3-chloro-4-methoxybenzyl)amino-1-(3-hydroxypyrrolidino)phthalazine;18)6-chloro-1-(4-ethoxycarbonylpiperidino)-4-(3,4-methylenedioxybenzyl)aminophthalazine;19)4-(3-chloro-4-methoxybenzyl)amino-1-[4-(2-hydroxyethyl)piperazin-1-yl]-6-nitrophthalazine;20)1-(3-chloro-4-methoxybenzyl)amino-6,7-dichloro-4-(4-ethoxycarbonylpiperidino)phthalazine;21)4-[4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazin-1-yl]thiomorpholine1,1-dioxide; 22)4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-[4-(methanesulfonamido)piperidino]phthalazine;23)4-(3-chloro-4-methoxybenzyl)amino-6-cyano-[(trans-4-hydroxy-1-cyclohexyl)amino]phthalazine;24) 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-piperidinophthalazine;25)4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(thio-morpholino)phthalazine;26)⁴-(3-chloro-4-methoxyanilino)-6-cyano-1-(4-hydroxy-piperidino)phthalazine;and 27)4-[2-(3-chloro-4-methoxyphenyl)ethylamino-6-cyano-1-(4-hydroxypiperidino)phthalazine.10. A method for treating female sexual dysfunction, dysmenorrhea orpremature birth which comprises administering an effective amount of afused pyridazine compound represented by the following formula (I) or apharmacologically acceptable salt thereof to a patient in need thereof:

wherein the ring C represents an unsaturated 5 or 6 membered ringoptionally having one heteroatom; n is 0 or an integer of from 1 to 4;R¹ represents a halogen, an optionally substituted lower alkyl, anoptionally substituted lower alkoxy, an optionally substitutedcycloalkyl, a nitro, a cyano, a group represented by the formula —NR²R³,wherein R² and R³ are the same as or different from each other andrepresent a hydrogen, an optionally substituted lower alkyl, an acyl, anoptionally substituted arylalkyl or an optionally substitutedheteroarylalkyl, or R² and R³ together with the nitrogen atom to whichthey are bonded may form a ring, and the ring may be substituted, agroup represented by the formula —O—R⁹, wherein R⁹ represents ahydrogen, an optionally substituted lower alkyl, acyl, an optionallysubstituted arylalkyl or an optionally substituted heteroarylalkyl, agroup represented by the formula —S—R¹⁰, wherein R¹⁰ represents ahydrogen, an optionally substituted lower alkyl, acyl, an optionallysubstituted arylalkyl or an optionally substituted heteroarylalkyl, agroup represented by the formula:

wherein R¹¹ represents a hydrogen, a lower alkyl or an amino; and m is 0or an integer of 1 or 2, or an optionally protected carboxy, providedthat when n is 2 to 4, then R¹s may independently represent the abovesubstituents; A represents a hydrogen, a halogen, a group represented bythe formula —NR⁴R⁵, wherein R⁴ and R⁵ are the same as or different fromeach other and represent a hydrogen, an optionally substituted loweralkyl, an acyl, an optionally substituted arylalkyl or an optionallysubstituted heteroarylalkyl, or R⁴ and R⁵ together with the nitrogenatom to which they are bonded may form a ring, and the ring may besubstituted, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted arylalkyl or an optionallysubstituted heteroarylalkyl; X represents a group represented by theformula —NR⁶—, wherein R⁶ represents a hydrogen, an optionallysubstituted lower alkyl, an optionally substituted arylalkyl or anoptionally substituted heteroarylalkyl or a group represented by theformula —N═; Y represents a group represented by the formula —CO— or—C(B)═, wherein B represents a hydrogen, a halogen, a group representedby the formula —NR⁷R⁸, wherein R⁷ and R⁸ are the same as or differentfrom each other and represent a hydrogen, an optionally substitutedlower alkyl, an acyl, an optionally substituted arylalkyl or anoptionally substituted heteroarylalkyl, or R⁷ and R⁸ together with thenitrogen atom to which they are bonded may form a ring, and the ring maybe substituted, a group represented by the formula —O—R¹², wherein R¹²represents a hydrogen, an optionally substituted lower alkyl, an acyl,an optionally substituted arylalkyl or an optionally substitutedheteroarylalkyl, a group represented by the formula —S—R¹³, wherein R¹³represents a hydrogen, an optionally substituted lower alkyl, an acyl,an optionally substituted arylalkyl or an optionally substitutedheteroarylalkyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted arylalkyl or anoptionally substituted heteroarylalkyl; and

represents a double or single bond; provided that when C is a benzenering, then the case where n is 0 is excluded.
 11. A medicinalcomposition which comprises a therapeutically effective dose of thefused pyridazine compound as set forth in claim 1 or a pharmacologicallyacceptable salt thereof and pharmacologically acceptable carriers.
 12. Amethod for treating erectile dysfunction, female sexual dysfunction,dysmenorrhea or premature birth which comprises administering atheraperutically effective dose of the fused pyridazine compound as setforth in claim 1 or a pharmacologically acceptable salt thereof to apatient with erectile dysfunction, female sexual dysfunction ordysmenorrhea or a patient giving premature birth.